Encapsulated bacteria such as Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae constitute a significant cause of morbidity and mortality in neonates and infants world-wide (Tunkel & Scheld, 1993). In developing countries, around one million children die each year due to pneumonia alone. Furthermore, even in developed countries, the increase in the phenomenon of antibiotic resistance means that there is a great need to improve on existing vaccines.
The polysaccharide capsule of H. influenzae, N. meningitidis and S. pneumoniae represents a major virulence factor that is important for nasopharyngeal colonisation and systemic invasion by encapsulated bacteria (Moxon and Kroll, 1990). Consequently, much of the research directed toward finding protective immunogens has focused on capsular polysaccharides. The finding that these polysaccharides are able to elicit the formation of protective antibodies led to the development of a number of vaccines that have been efficacious in protecting adults from disease (Andreoni et al. 1993; Goldblatt et al. 1992).
The problem with capsular polysaccharide vaccines developed to date is that they suffer an inherent inability to protect children under two years of age from disease (Holmes and Granoff 1992). This is a significant drawback when it is appreciated that this population of children is at highest risk of infection. Their failure to block infection is believed to derive from the T-cell independent (TI) type of immune reaction that is the only antibody response used by the body against polysaccharide antigens. This type of response does not involve MHC Class II restriction molecules for antigen presentation to T-cells; as a consequence, T-cell help is prevented. Although the TI response works well in adults, it is inactive in very young children due to a combination of factors such as functional B-cell immaturity, inactivation of B-cell receptor-mediated signalling and B-cell anergy in response to antigen stimulation.
To overcome this drawback, two particular vaccine approaches are currently being investigated. The first is the development of anti-idiotype vaccines that contain peptides that mimic carbohydrate idiotypes (McNamara 1984; Agadjanyan, 1997). The second approach involves conjugate vaccines that are designed to transform T-cell independent (TI) polysaccharide antigens into T-dependent (TD) antigens through the covalent linkage of the polysaccharide to a peptide carrier.
H. influenzae type B (Hib) conjugate vaccines represent a leading example for the development of other vaccines against infections that are due to capsulated bacteria. In fact, meningitis and other infections caused by Hib have declined dramatically in countries where widespread vaccination with Hib conjugate has been achieved (Robins, 1996). Complete elimination of the pathogen might be possible, but depends upon several factors, including a further improvement of the existing vaccines (Liptak, 1997).
The widely distributed paediatric vaccine antigens tetanus and diptheria toxoids have been selected as carrier proteins with the aim of taking advantage of an already-primed population at the time of conjugate vaccine injection. Previous vaccination with paediatric diptheria-tetanus (DT) or diptheria-tetanus-pertussis (DTP) vaccines means that carrier priming may now be exploited to enhance the immune response to polysaccharide conjugates.
A number of such vaccines have been successfully produced and have been efficacious in reducing the number of deaths caused by these pathogens. The carriers used in these vaccines are large antigens such as tetanus toxoid, non-toxic diptheria toxin mutant CRM197 and group B N. meningitidis outer membrane protein complex (OMPC). However, in the future, it is thought that as the number of conjugate vaccines containing the same carrier proteins increases, the suppression of immune responses by pre-existing antibodies to the carrier is likely to become a problem.
Much research is now being directed to the development of improved carrier molecules that contain carrier peptides comprising CD4+ T helper cell (Th) epitopes, but which do not possess T-cell suppressive (Ts) functions (Etlinger et al. 1990). Peptides which retain only helper functions (CD4+ epitopes) are most suitable as carriers, since their effect is sufficient to induce T cell help but the carrier is small enough to limit or to completely avoid production of anti-carrier antibodies.
Various publications demonstrate the ability of such peptides to confer T-cell help to haptens when covalently linked to them (Etlinger, 1990; Valmori 1992; Sadd 1992; Kumar 1992; Kaliyaperumal, 1995; De Velasco, 1995 and Bixler 1989). However, to date, these publications have not resulted in the development of effective vaccines. There thus remains a great need for the development of new, improved vaccine strategies that are effective in combating diseases caused by encapsulated bacteria in infants and young children.